Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation

Author(s):Show less -

Stanley, Christopher P. ^[1] ; Maghzal, Ghassan J. ^{[1, 2]} ; Ayer, Anita ^{[1, 2]} ; Talib, Jihan ^{[1, 2]} ; Giltrap, Andrew M. ^[3] ; Shengule, Sudhir ^[1] ; Wolhuter, Kathryn ^[1] ; Wang, Yutang ^{[4, 5, 6]} ; Chadha, Preet ^[1] ; Suarna, Cacang ^[1] ; Prysyazhna, Oleksandra ^{[7, 8]} ; Scotcher, Jenna ^{[7, 8]} ; Dunn, Louise L. ^[1] ; Prado, Fernanda M. ^[9] ; Nguyen, Nghi ^[10] ; Odiba, Jephthah O. ^[10] ; Baell, Jonathan B. ^{[10, 11]} ; Stasch, Johannes-Peter ^[12] ; Yamamoto, Yorihiro ^[13] ; Di Mascio, Paolo ^[9] ; Eaton, Philip ^{[7, 8]} ; Payne, Richard J. ^[3] ; Stocker, Roland ^{[1, 2]}

Affiliation:Show less -

^[1] Victor Chang Cardiac Res Inst, Darlinghurst, NSW - Australia

^[2] Univ New South Wales, St Vincents Clin Sch, Sydney, NSW - Australia

^[3] Univ Sydney, Sch Chem, Sydney, NSW - Australia

^[4] Univ Sydney, Sch Med Sci Pathol, Ctr Vasc Res, Sydney, NSW - Australia

^[5] Univ Sydney, Sydney Med Sch, Bosch Inst, Sydney, NSW - Australia

^[6] Federat Univ Australia, Sch Hlth & Life Sci, Ballarat, Vic - Australia

^[7] Kings Coll London, Cardiovasc Div, Dept Cardiol, London - England

^[8] St Thomas Hosp, Rayne Inst, London - England

^[9] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil

^[10] Monash Univ, Monash Inst Pharmaceut Sci, Med Chem, Parkville, Vic - Australia

^[11] Nanjing Tech Univ, Sch Pharmaceut Sci, Nanjing, Jiangsu - Peoples R China

^[12] Bayer AG, Cardiovasc Res, Wuppertal - Germany

^[13] Tokyo Univ Technol, Sch Biosci & Biotechnol, Tokyo - Japan

• Document type: Journal article
• Source: Nature; v. 566, n. 7745, p. 548+, FEB 28 2019.
• Web of Science Citations: 9

Abstract

Singlet molecular oxygen (O-1(2)) has well-established roles in photosynthetic plants, bacteria and fungi(1-3), but not in mammals. Chemically generated O-1(2) oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine(4), whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1(5). Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure(6). However, whether indoleamine 2,3-dioxygenase 1 forms O-1(2) and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of O-1(2). We observed that in the presence of hydrogen peroxide, the enzyme generates O-1(2) and that this is associated with the stereoselective oxidation of L-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1 alpha. Our findings demonstrate a pathophysiological role for O-1(2) in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions. (AU)

• FAPESP's process: 12/12663-1 - Singlet molecular oxygen and peroxides in chemical biology
• Grantee: Paolo Di Mascio
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC